Transcription factor regulation as a mechanism of confounding effects between distinct human traits [version 1; referees: 1 not approved]

Genome-wide association studies (GWAS) to date have discovered thousands of genetic variants linked to human diseases and traits, which hold the potential to unravel the mechanisms of complex phenotypes. However, given that the majority of these associated variants reside in non-coding genomic regions, their predicted and -regulatory functions remain largely undefined. cis trans Here we show that correlation between human diseases and traits can follow geographical distribution of human populations, and that the underlying mechanism is at least partly genetically based. We report two Type 2 Diabetes (T2D) GWAS variants (rs7903146 and rs12255372) in the locus that TCF7L2 regulate expression in skin tissues but not lymphoblastoid or adipose tissues, of the gene that encodes an important regulator of melanogenesis and KITLG light hair color in European populations. We also report extensive binding events of TCF7L2 protein in the promoter region, immediate upstream region and first intron of the gene, which supports a -interaction between KITLG trans and . We further show that both light hair color and T2D genetic TCF7L2 KITLG variants are correlated with geographic latitude. Taken together, our observations suggest that natural variation in transcription factor loci in European human populations may be an underlying and confounding factor for the geographical correlation between human phenotypes, such as type 2 diabetes and light hair color. We postulate that transcription factor regulation may confound the correlation between seemingly diverse human traits. Furthermore, our findings demonstrate the importance of dissecting the genomic architecture of GWAS loci using multiple genetic and genomic datasets. * *